Modeling antimicrobial tolerance and treatment of heterogeneous biofilms

Abstract

Biofilms are known to be more persistent to antimicrobial treatment than planktonic bacterial cells. In addition to the protective extracellular matrix formed primarily by expopolysaccharides (EPS), one of the current point of views on this issue is that there may exist a small portion of phenotypic bacterial variants, known as persisters, which are invulnerable to antimicrobial treatment, while the majority of the bacterial cells is susceptible to antimicrobial treatment. In this paper, a multiphasic, hydrodynamic model for spatially heterogeneous biofilms based on the phase field formulation is proposed and applied to analyze the mechanism of antimicrobial persistence of biofilms by acknowledging the existence of persisters and susceptible cells in the total population of bacteria and to investigate the impact of hydrodynamics during antimicrobial treatment. An improved switching mechanism between the persister and susceptible cells is proposed. A numerical scheme is devised to solve the model consisting of partial differential equations, which is implemented on graphic processing units (GPUs) for high performance computing in 3-D space and time. Antimicrobial treatment in an infinitely long quiescent water channel and in a short water tube under inflow and outflow boundary conditions are simulated respectively using the model, in which multiple antibiotic dosing locations and strategies are investigated. The model can predict the internal spatial and temporal distribution of bacteria, EPS, nutrient and antimicrobial agents during antimicrobial treatment, providing a useful tool for analyzing the mechanism of biofilm persistence to antimicrobial treatment in an aqueous environment. The numerical result shows the mechanism of conversion between the susceptible bacteria and persisters is essential for dynamics of persisters and thereby biofilm growth.